This invention relates to thioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid derivatives, therapeutically acceptable salts thereof, a process for their preparation and to pharmaceutical compositions thereof. The derivatives have pharmacologic properties which render them beneficial for the treatment of diabetes mellitus and associated conditions.
For many years diabetes mellitus has been treated with two established types of drugs, namely insulin and oral hypoglycemic agents. These drugs have benefited hundreds of thousands of diabetics by improving their well-being and prolonging their lives. However, the resulting longevity of diabetic patients has led to complications such as neuropathy, nephropathy, retinopathy and cataracts. These complications have been linked to the undesirable accumulation of sorbitol in diabetic tissue, which is turn result from the high levels of glucose characteristic of the diabetic patient.
In mammals, including humans, the key enzyme involved in the conversion of hexoses to polyols (the sorbitol pathway) is aldose reductase. J. H. Kinoshita and collaborators, see J. H. Kinoshita, et al., Biochem. Biophys. Acta., 158, 472 (1968) and references cited therein, have demonstrated that aldose reductase plays a central role in the etiology of galactosemic cataracts by effecting the conversion of galactose to dulcitol (galactitol) and that an agent capable of inhibiting aldose reductase can prevent the detrimental accumulation of dulcitol in the lens. Furthermore, a relationship between elevated levels of glucose and an undesirable accumulation of sorbitol has been demonstrated in the lens, peripheral nervous cord and kidney of diabetic animals, see A. Pirie and R. van Heyningen, Exp. Eye Res., 3,124 (1964); L. T. Chylack and J. H. Kinoshita, Invest. Ophthal., 8, 401 (1969) and J. D. Ward and R. W. R. Baker, Diabetol., 6, 531 (1970).
1,3-Dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid has been reported to be an effective inhibitor of aldose reductase, see D. Dvornik et al., Science, 182, 1146 (1973), and to be useful for the treatment of diabetic complications such as diabetic cataracts, neuropathy, nephropathy and retinopathy, see K. Sestanj, N. Simard-Duquesne and D. M. Dvornik, U.S. Pat. No. 3,821,383, June 28, 1974. This compound also stimulates insulin release while inhibiting glucagon secretion, see W. Lippmann, U.S. Pat. No. 4,118,495, Oct. 3, 1978. Accordingly, this compound represents an important adjunct to the treatment of diabetes mellitus. U.S. Pat. No. 3,821,383 also discloses the 5-nitro, 5-amino and 6-bromo derivatives of 1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid.
The present Application discloses a new group of sulfur substituted 1H-benz[de]isoquinoline compounds. The new compounds are more effective than 1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid and the related derivatives, disclosed in U.S. Pat. No. 3,821,383, in inhibiting aldose reductase and in stimulating insulin release while inhibiting glucagon. Furthermore, the new compounds are longer acting. Sulfur substituted 1H-benz[de]isoquinolines have been described by P. H. Grayshan et al., J. Heterocycl. Chem., 11, 33 (1974) and by T. Shirosaki, see Chem. Abstr., 86, 89467d (1977) for Japanese Patent Kokai No. 76/109,020, Sept. 27, 1976; however these prior art compounds are distinguished from compounds of the present Application by having sulfur in different oxidation states or by having completely different substituents. Furthermore, a common feature of the compounds of this invention, not shared by prior art compounds, is that they are thioxo-1H-benz[de]isoquinoline derivatives. These thioxo-1H-benz[d]isoquinoline derivatives are prepared by a process whereby an intermediate 1,3-dioxo-1H-benz[de]isoquinoline derivative is reacted with phosphorus pentasulfide. A prior art search indicates that the latter derivatives never have been subjected to phosphorus pentasulfide, although several years ago, R. J. W. Cremlyn, J. Chem. Soc., 5055 (1961) prepared a series of thiophthalimides by reacting corresponding phthalimides with phosphorus pentasulfide.